Title: “Regulating mRNA translation drives prostate cancer progression”
Abstract: The acquisition of oncogenic insults stimulates bioenergetically demanding processes including an increase in protein synthesis to drive cancer cell growth and tumor development. The hijacking of these key cellular processes by oncogenic pathways imposes a burden of stress on cancer cells that requires an adaptive or evasive response for continuous cell survival. How these active response programs are established and what their functional consequences are for tumor development with therapeutic interventions has remain largely unknown.
Through the investigation into how oncogenic drivers independently enhance protein synthesis for cancer cell growth, I unexpectedly discovered that key oncogenic events cooperate for a necessary ‘brake’ for global protein synthesis during aggressive prostate cancer (PrCa) development. Within mouse and humanized models of PrCa, our team demonstrated that the phosphorylation of an initiation factor, P-eIF2α, is an important node of this adaptive response that rewires global protein synthesis upon oncogenic stress and is associated with worse prognosis and decreased patient survival. Our research has opened a new gateway into understanding how translational re-programming maintains the adaptation of oncogenic cells to combat proteotoxic stress for growth, while developing therapeutic approaches to target stress responses occurring during cancer progression. The Conn lab is focused on identifying the distinct mRNA targets that are rapidly translated through these adaptive signaling responses: how are they recognized for translation when global protein synthesis is halted, are there non-canonical functions of the proteins synthesized, and are unique peptides translated for distinct oncogenic signaling? Our ongoing studies will provide insight into RNA biology, identifying how oncogenic and nutrient signaling pathways directly reconstitute gene expression through translational control in order to maintain cellular homeostasis for cancer cell survival with promise to guide new avenues for therapeutic applications.
